Heparin-induced thrombocytopenia/thrombosis (HITP) is an important cause of morbidity and mortality in patients receiving heparin therapy. Despite numerous studies, the molecular basis for thrombocytopenia and the mechanism(s) responsible for the associated thrombosis and disseminated intravascular coagulation (DIC) are poorly understood. Studies by the applicant and those of several other groups have shown that antibodies associated with HITP are specific for molecular complexes consisting of heparin, or other glycosaminoglycans (GAG) and platelet factor 4 (PF4). This application describes a series of studies to characterize the molecular mechanisms involved in the pathogenesis of HITP and to develop improved methods for diagnosis and treatment. The proposed studies address three areas relevant to HITP pathogenesis: l) identification of the epitopes on the heparin: PF4 complex that are recognized by HITP antibodies, using a variety of molecular genetic and immunochemical techniques; 2) characterization of the mechanisms by which heparin-induced antibodies activate resting platelets and promote their destruction; and 3) characterization of PF4-dependent binding of HTIP antibodies to endothelial cells to induce structural and functional changes that may explain the thrombotic tendency in HITP. Findings made in the course of these studies may lead to improved methods for treating and preventing HITP. They may also add to the understanding of other drug-induced hematologic disorders. The candidate trained in Medicine and Pathology at the University of Naples and held a clinical position in Italy before relocating to the U.S. in 1992, where he is now beginning an academic career with an emphasis on research related to transfusion medicine. He plans to further develop his basic and clinical research skills under the guidance of two senior investigators: Drs. Richard Aster (Primary Sponsor) and Peter Newman (Secondary Sponsor). His long-term goal is to become an independent biomedical scientist who will pursue an academic research career in transfusion medicine. The proposed studies will be performed within the Blood Research Institute of The Blood Center of Southeastern Wisconsin, where necessary space, equipment, consultation, and supporting services are available to him. The Blood Research Institute (BRI) houses a family of core support laboratories and a group of investigators with diverse interests who can provide advice and encouragement to the candidate. Numerous conferences and seminars are held throughout the year at the BRI and the nearby Medical College of Wisconsin. This environment should be ideal for the candidate's development as an investigator.